title: Structural simplification of bioactive natural products with multicomponent synthesis. 3. Fused uracil-containing heterocycles as novel topoisomerase-targeting agents.
abstract: After the initial discovery of antiproliferative and apoptosis-inducing properties of a camptothecin-inspired pentacycle based on a 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine scaffold, a library of its analogues as well as their oxidized planar counterparts were prepared utilizing a practical multicomponent synthetic protocol. The synthesized compounds exhibited submicromolar to low micromolar antiproliferative potencies toward a panel of human cancer cell lines. Biochemical experiments are consistent with the dihydropyridine library members undergoing intracellular oxidation to the corresponding planar pyridines, which then inhibit topoisomerase II activity, leading to inhibition of proliferation and cell death. Because of facile synthetic preparation and promising antitopoisomerase activity, both the dihydropyridine and planar pyridine-based compounds represent a convenient starting point for anticancer drug discovery.
authors.affiliation: Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801, United States.
authors.forename: Nikolai M
authors.initials: NM
authors.lastname: Evdokimov
authors.forename: Severine
authors.initials: S
authors.lastname: Van Slambrouck
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Lee
authors.initials: L
authors.lastname: Tu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Le Calvé
authors.forename: Delphine
authors.initials: D
authors.lastname: Lamoral-Theys
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Hooten
authors.forename: Pavel Y
authors.initials: PY
authors.lastname: Uglinskii
authors.forename: Snezna
authors.initials: S
authors.lastname: Rogelj
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.forename: Wim F A
authors.initials: WF
authors.lastname: Steelant
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Cristian G
authors.initials: CG
authors.lastname: Bologa
authors.forename: Alexander
authors.initials: A
authors.lastname: Kornienko
authors.forename: Igor V
authors.initials: IV
authors.lastname: Magedov
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014498:Uracil / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D059005:Topoisomerase II Inhibitors; D014498:Uracil; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II